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Nature Reviews. Cancer Jul 2018The recent advances in in vitro 3D culture technologies, such as organoids, have opened new avenues for the development of novel, more physiological human cancer models.... (Review)
Review
The recent advances in in vitro 3D culture technologies, such as organoids, have opened new avenues for the development of novel, more physiological human cancer models. Such preclinical models are essential for more efficient translation of basic cancer research into novel treatment regimens for patients with cancer. Wild-type organoids can be grown from embryonic and adult stem cells and display self-organizing capacities, phenocopying essential aspects of the organs they are derived from. Genetic modification of organoids allows disease modelling in a setting that approaches the physiological environment. Additionally, organoids can be grown with high efficiency from patient-derived healthy and tumour tissues, potentially enabling patient-specific drug testing and the development of individualized treatment regimens. In this Review, we evaluate tumour organoid protocols and how they can be utilized as an alternative model for cancer research.
Topics: Adult Stem Cells; Biomedical Research; Gene Editing; Humans; Models, Biological; Neoplasms; Organoids; Phenotype; Tissue Culture Techniques; Translational Research, Biomedical
PubMed: 29692415
DOI: 10.1038/s41568-018-0007-6 -
Circulation Research Sep 2017Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is characterized by left ventricular hypertrophy unexplained by secondary causes and a nondilated left... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is characterized by left ventricular hypertrophy unexplained by secondary causes and a nondilated left ventricle with preserved or increased ejection fraction. It is commonly asymmetrical with the most severe hypertrophy involving the basal interventricular septum. Left ventricular outflow tract obstruction is present at rest in about one third of the patients and can be provoked in another third. The histological features of HCM include myocyte hypertrophy and disarray, as well as interstitial fibrosis. The hypertrophy is also frequently associated with left ventricular diastolic dysfunction. In the majority of patients, HCM has a relatively benign course. However, HCM is also an important cause of sudden cardiac death, particularly in adolescents and young adults. Nonsustained ventricular tachycardia, syncope, a family history of sudden cardiac death, and severe cardiac hypertrophy are major risk factors for sudden cardiac death. This complication can usually be averted by implantation of a cardioverter-defibrillator in appropriate high-risk patients. Atrial fibrillation is also a common complication and is not well tolerated. Mutations in over a dozen genes encoding sarcomere-associated proteins cause HCM. and , encoding β-myosin heavy chain and myosin-binding protein C, respectively, are the 2 most common genes involved, together accounting for ≈50% of the HCM families. In ≈40% of HCM patients, the causal genes remain to be identified. Mutations in genes responsible for storage diseases also cause a phenotype resembling HCM (genocopy or phenocopy). The routine applications of genetic testing and preclinical identification of family members represents an important advance. The genetic discoveries have enhanced understanding of the molecular pathogenesis of HCM and have stimulated efforts designed to identify new therapeutic agents.
Topics: Animals; Biopsy; Cardiac Imaging Techniques; Cardiomyopathy, Dilated; DNA Mutational Analysis; Genetic Markers; Genetic Predisposition to Disease; Humans; Molecular Diagnostic Techniques; Mutation; Myocardium; Phenotype; Predictive Value of Tests; Prognosis; Risk Assessment; Risk Factors; Ventricular Function, Left
PubMed: 28912181
DOI: 10.1161/CIRCRESAHA.117.311059 -
Journal of Internal Medicine Jun 2020Mitochondrial disease presenting in childhood is characterized by clinical, biochemical and genetic complexity. Some children are affected by canonical syndromes, but... (Review)
Review
Mitochondrial disease presenting in childhood is characterized by clinical, biochemical and genetic complexity. Some children are affected by canonical syndromes, but the majority have nonclassical multisystemic disease presentations involving virtually any organ in the body. Each child has a unique constellation of clinical features and disease trajectory, leading to enormous challenges in diagnosis and management of these heterogeneous disorders. This review discusses the classical mitochondrial syndromes presenting most frequently in childhood and then presents an organ-based perspective including systems less frequently linked to mitochondrial disease, such as skin and hair abnormalities and immune dysfunction. An approach to diagnosis is then presented, encompassing clinical evaluation and biochemical, neuroimaging and genetic investigations, and emphasizing the problem of phenocopies. The impact of next-generation sequencing is discussed, together with the importance of functional validation of novel genetic variants never previously linked to mitochondrial disease. The review concludes with a brief discussion of currently available and emerging therapies. The field of mitochondrial medicine has made enormous strides in the last 30 years, with approaching 400 different genes across two genomes now linked to primary mitochondrial disease. However, many important questions remain unanswered, including the reasons for tissue specificity and variability of clinical presentation of individuals sharing identical gene defects, and a lack of disease-modifying therapies and biomarkers to monitor disease progression and/or response to treatment.
Topics: Child; Humans; Mitochondria; Mitochondrial Diseases; Mutation; Phenotype
PubMed: 32176382
DOI: 10.1111/joim.13054 -
The Journal of Allergy and Clinical... Jun 2023Autoimmunity may be a manifestation of inborn errors of immunity, specifically as part of the subgroup of primary immunodeficiency known as primary immune regulatory... (Review)
Review
Autoimmunity may be a manifestation of inborn errors of immunity, specifically as part of the subgroup of primary immunodeficiency known as primary immune regulatory disorders. However, although making a single gene diagnosis can have important implications for prognosis and management, picking patients to screen can be difficult, against a background of a high prevalence of autoimmune disease in the population. This review compares the genetics of common polygenic and rare monogenic autoimmunity, and explores the molecular mechanisms, phenotypes, and inheritance of autoimmunity associated with primary immune regulatory disorders, highlighting the emerging importance of gain-of-function and non-germline somatic mutations. A novel framework for identifying rare monogenic cases of common diseases in children is presented, highlighting important clinical and immunologic features that favor single gene disease and guides clinicians in selecting appropriate patients for genomic screening. In addition, there will be a review of autoimmunity in non-genetically defined primary immunodeficiency such as common variable immunodeficiency, and of instances where primary autoimmunity can result in clinical phenocopies of inborn errors of immunity.
Topics: Humans; Autoimmune Diseases; Immunologic Deficiency Syndromes; Autoimmunity; Common Variable Immunodeficiency
PubMed: 37119983
DOI: 10.1016/j.jaip.2023.04.018 -
Biochimica Et Biophysica Acta.... Apr 2022ARPKD is a genetically inherited kidney disease that manifests by bilateral enlargement of cystic kidneys and liver fibrosis. It shows a range of severity, with 30% of... (Review)
Review
ARPKD is a genetically inherited kidney disease that manifests by bilateral enlargement of cystic kidneys and liver fibrosis. It shows a range of severity, with 30% of individuals dying early on and the majority having good prognosis if they survive the first year of life. The reasons for this variability remain unclear. Two genes have been shown to cause ARPKD when mutated, PKHD1, mutations in which lead to most of ARPKD cases and DZIP1L, which is associated with moderate ARPKD. This mini review will explore the genetics of ARPKD and discuss potential genetic modifiers and phenocopies that could affect diagnosis.
Topics: Adaptor Proteins, Signal Transducing; Animals; Humans; Polycystic Kidney, Autosomal Recessive; Polymorphism, Genetic; Prognosis; Receptors, Cell Surface; Signal Transduction; Transcription Factors
PubMed: 35032595
DOI: 10.1016/j.bbadis.2022.166348 -
Nature Reviews. Neuroscience May 2021Evidence from human genetic pain disorders shows that voltage-gated sodium channel α-subtypes Nav1.7, Nav1.8 and Nav1.9 are important in the peripheral signalling of... (Review)
Review
Evidence from human genetic pain disorders shows that voltage-gated sodium channel α-subtypes Nav1.7, Nav1.8 and Nav1.9 are important in the peripheral signalling of pain. Nav1.7 is of particular interest because individuals with Nav1.7 loss-of-function mutations are congenitally insensitive to acute and chronic pain, and there is considerable hope that phenocopying these effects with a pharmacological antagonist will produce a new class of analgesic drug. However, studies in these rare individuals do not reveal how and where voltage-gated sodium channels contribute to pain signalling, which is of critical importance for drug development. More than a decade of research utilizing rodent genetic models and pharmacological tools to study voltage-gated sodium channels in pain has begun to unravel the role of different subtypes. Here, we review the contribution of individual channel subtypes in three key physiological processes necessary for transmission of sensory information to the CNS: transduction of stimuli at peripheral nerve terminals, axonal transmission of action potentials and neurotransmitter release from central terminals. These data suggest that drugs seeking to recapitulate the analgesic effects of loss of function of Nav1.7 will need to be brain-penetrant - which most of those developed to date are not.
Topics: Animals; Humans; NAV1.7 Voltage-Gated Sodium Channel; Pain; Voltage-Gated Sodium Channels
PubMed: 33782571
DOI: 10.1038/s41583-021-00444-w -
The American Journal of the Medical... Jun 2021Diabetic ketoacidosis (DKA) is a serious complication of diabetes mellitus. Hyperglycemia, acidosis, and electrolyte imbalances can directly affect the heart by inducing... (Review)
Review
Diabetic ketoacidosis (DKA) is a serious complication of diabetes mellitus. Hyperglycemia, acidosis, and electrolyte imbalances can directly affect the heart by inducing toxicity, impairing myocardial blood flow, autonomic dysfunction, and altering activation and conduction of electrical impulses throughout the heart, increasing the risk of arrhythmias and ischemia. The electrocardiogram is useful in monitoring patients during and after an episode of DKA, as it allows the detection of arrhythmias and guides metabolic correction. Unfortunately, reports on electrocardiographic abnormalities in patients with DKA are lacking. We found two electrocardiographic patterns that are frequently reported in the literature: a pseudo-myocardial infarction and a Brugada Phenocopy. Both are associated with DKA metabolic anomalies and they resolve after treatment. Because of their clinical relevance and the challenge they represent for clinicians, we analyzed the clinical characteristics of these patients and the mechanisms involved in these electrocardiographic findings.
Topics: Acute Disease; Arrhythmias, Cardiac; Diabetic Ketoacidosis; Electrocardiography; Heart Rate; Humans
PubMed: 33941367
DOI: 10.1016/j.amjms.2020.11.030 -
Cell May 2015Most cancer cells release heterogeneous populations of extracellular vesicles (EVs) containing proteins, lipids, and nucleic acids. In vitro experiments showed that EV...
Most cancer cells release heterogeneous populations of extracellular vesicles (EVs) containing proteins, lipids, and nucleic acids. In vitro experiments showed that EV uptake can lead to transfer of functional mRNA and altered cellular behavior. However, similar in vivo experiments remain challenging because cells that take up EVs cannot be discriminated from non-EV-receiving cells. Here, we used the Cre-LoxP system to directly identify tumor cells that take up EVs in vivo. We show that EVs released by malignant tumor cells are taken up by less malignant tumor cells located within the same and within distant tumors and that these EVs carry mRNAs involved in migration and metastasis. By intravital imaging, we show that the less malignant tumor cells that take up EVs display enhanced migratory behavior and metastatic capacity. We postulate that tumor cells locally and systemically share molecules carried by EVs in vivo and that this affects cellular behavior.
Topics: Animals; Cell Line, Tumor; Humans; Integrases; Mice; Neoplasm Metastasis; Neoplastic Cells, Circulating; Transport Vesicles
PubMed: 26000481
DOI: 10.1016/j.cell.2015.04.042 -
Heart Failure Reviews Jul 2022The comprehensive assessment of patients with hypertrophic cardiomyopathy is a complex process, with each step concurrently focusing on confirmation of the diagnosis,... (Review)
Review
The comprehensive assessment of patients with hypertrophic cardiomyopathy is a complex process, with each step concurrently focusing on confirmation of the diagnosis, differentiation between sarcomeric and non-sarcomeric disease (phenocopy), and prognostication. Novel modalities such as genetic testing and advanced imaging have allowed for substantial advancements in the understanding of this condition and facilitate patient management. However, their availability is at present not universal, and interpretation requires a high level of expertise. In this setting, electrocardiography, a fast and widely available method, still retains a significant role in everyday clinical assessment of this population. In our review, we follow a stepwise approach for the interpretation of each electrocardiographic segment, discussing clinical implications of electrocardiographic patterns in sarcomeric disease, their value in the differential diagnosis from phenocopies, and impact on patient management. Outlining the substantial amount of information to be obtained from a simple tracing, we exhibit how electrocardiography is likely to remain an integral diagnostic tool in the future as well.
Topics: Cardiomyopathy, Hypertrophic; Diagnosis, Differential; Electrocardiography; Genetic Testing; Humans; Phenotype
PubMed: 34286451
DOI: 10.1007/s10741-021-10147-0 -
American Journal of Physiology.... Apr 2019The liver is a critical tissue for maintaining glucose, fatty acid, and cholesterol homeostasis. Primary hepatocytes represent the gold standard for studying the...
The liver is a critical tissue for maintaining glucose, fatty acid, and cholesterol homeostasis. Primary hepatocytes represent the gold standard for studying the mechanisms controlling hepatic glucose, lipid, and cholesterol metabolism in vitro. However, access to primary hepatocytes can be limiting, and therefore, other immortalized hepatocyte models are commonly used. Here, we describe substrate metabolism of cultured AML12, IHH, and PH5CH8 cells, hepatocellular carcinoma-derived HepG2s, and primary mouse hepatocytes (PMH) to identify which of these cell lines most accurately phenocopy PMH basal and insulin-stimulated metabolism. Insulin-stimulated glucose metabolism in PH5CH8 cells, and to a lesser extent AML12 cells, responded most similarly to PMH. Notably, glucose incorporation in HepG2 cells were 14-fold greater than PMH. The differences in glucose metabolic activity were not explained by differential protein expression of key regulators of these pathways, for example glycogen synthase and glycogen content. In contrast, fatty acid metabolism in IHH cells was the closest to PMHs, yet insulin-responsive fatty acid metabolism in AML12 and HepG2 cells was most similar to PMH. Finally, incorporation of acetate into intracellular-free cholesterol was comparable for all cells to PMH; however, insulin-stimulated glucose conversion into lipids and the incorporation of acetate into intracellular cholesterol esters were strikingly different between PMHs and all tested cell lines. In general, AML12 cells most closely phenocopied PMH in vitro energy metabolism. However, the cell line most representative of PMHs differed depending on the mode of metabolism being investigated, and so careful consideration is needed in model selection.
Topics: Acetates; Animals; Cell Line; Cholesterol; Cholesterol Esters; Fatty Acids; Glucose; Hep G2 Cells; Hepatocytes; Humans; Hypoglycemic Agents; In Vitro Techniques; Insulin; Lipid Metabolism; Mice; Primary Cell Culture
PubMed: 30694691
DOI: 10.1152/ajpendo.00365.2018